Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions

Abstract

The molecular diagnosis of mitochondrial disorders still remains elusive in a large proportion of patients, but advances in next generation sequencing are significantly improving our chances to detect mutations even in sporadic patients. Syndromes associated with mitochondrial DNA multiple deletions are caused by different molecular defects resulting in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia to multi-systemic disorders of variable severity. The mutations underlying these conditions remain undisclosed in half of the affected subjects. We applied next-generation sequencing of known mitochondrial targets (MitoExome) to probands presenting with adult-onset mitochondrial myopathy and harbouring mitochondrial DNA multiple deletions in skeletal muscle. We identified autosomal recessive mutations in the DGUOK gene (encoding mitochondrial deoxyguanosine kinase), which has previously been associated with an infantile hepatocerebral form of mitochondrial DNA depletion. Mutations in DGUOK occurred in five independent subjects, representing 5.6% of our cohort of patients with mitochondrial DNA multiple deletions, and impaired both muscle DGUOK activity and protein stability. Clinical presentations were variable, including mitochondrial myopathy with or without progressive external ophthalmoplegia, recurrent rhabdomyolysis in a young female who had received a liver transplant at 9 months of age and adult-onset lower motor neuron syndrome with mild cognitive impairment. These findings reinforce the concept that mutations in genes involved in deoxyribonucleotide metabolism can cause diverse clinical phenotypes and suggest that DGUOK should be screened in patients harbouring mitochondrial DNA deletions in skeletal muscle.

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…Affected individuals with this form may develop mild hypotonia and renal involvement manifesting as proteinuria and aminoaciduria [2,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. More recently, DGUOK mutations have been reported in a neonate with clinical and autopsy findings consistent with neonatal hemochromatosis and mtDNA depletion [56], and in individuals with adult-onset mitochondrial myopathy and mtDNA multiple deletions in skeletal muscle [57].…”

Multiple Deletions in Mitochondrial DNA in a Patient with Progressive External Ophthalmoplegia, Leukoencephalopathy and Hypogonadism

“…Most sporadic PEO patients have a heteroplasmic large deletion of mtDNA in the muscle. In patients with multiple mtDNA deletions, additional clinical features may be present, such as sensory axonal neuropathy, optic atrophy, ataxia, hypogonadism and parkinsonism (2,3). Mutations in nuclear genes, such as POLG1 and POLG2 (DNA polymerase gamma) (4,5), PEO1 (the helicase Twinkle) (6) and SLC25A4 (other alias: ANT1, the adenine nucleotide translocator) (7), have thus far been identified as driving multiple mtDNA deletion genes in PEO patients (2,3).…”

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

“…Most of these cases are caused by mutations in nuclear genes directly involved in mtDNA replication and maintenance, that is, POLG 3 and POLG2 ,4 encoding the 2 subunits of mtDNA polymerase, C10orf2 ,5 encoding the mtDNA helicase Twinkle, and DNA2 ,6 encoding an mtDNA helicase/nuclease. Mutations in genes that control the mitochondrial nucleotide pools can also be associated with this phenotype, including SLC25A4 ,7 encoding the heart/muscle‐specific adenine nucleotide translocator ANT1, TYMP ,8 encoding thymidine phosphorylase, TK2 ,9 encoding the mitochondrial thymidine kinase, RRM2B ,10 encoding the p53‐sensitive subunit of ribonucleoside reductase, and DGUOK ,11 encoding mitochondrial deoxyguanosine kinase. A further gene associated with mtDNA depletion and multiple deletions is MPV17 ,12 for which the protein function remains unclear.…”